This proposal describes a five-year training program aimed at developing research expertise that integrates neural, stem cell and systems biology. The applicant is a MD/PhD who will have completed pathology residency and clinical obligations for a transfusion medicine fellowship at Harvard Medical School prior to the proposed start date. The candidate's clinical interests are in the area of stem cell therapy, especially in the isolation, culturing, and manipulation of human somatic stem cells. He is currently receiving basic science training under the mentorship of Dr. Rudolf Jaenisch, a world-renowned expert on stem cells, cellular reprogramming, and developmental biology. Dr. Leslie Silberstein, head of the Harvard Transfusion Medicine program, will co-mentor the applicant during the proposed training period facilitating applicant's transition into an independent investigator. An advisory committee of highly respected physician and basic scientists will provide experimental insight and career guidance. The applicant is committed to an academic career in scientific research combining the skills he will develop as a researcher and clinician during the training period. The goal of the proposed research is to analyze the epigenetics of the neural stem cell fate and identify genes involved in the process. Neural stem cells hold great promise in the field of regenerative medicine including the treatment of neurodegenerative diseases and neural injury. However, very little is known about the biology of these cells. To maximize the clinical effectiveness of neural stem cells, it will be important to determine the nature of the genome that provides and at the same time limits their developmental potential. The candidate will use a combination of nuclear transfer techniques, expression and chromatin profiling, and functional testing of candidate genes in the mouse model system to address this problem. Nuclear transfer provides a global and unbiased method to reprogram the neural stem cell to a pluripotent state. Combined with expression and chromatin profiling, nuclear transfer can help identify candidate genes and epigenetic marks that determine the multipotent neural versus the pluripotent embryonic stem cell fate. Established genetic tools for ectopically expressing and knocking down gene function provide means to test the role of these candidate potency genes. This line of research should provide conceptual and therapeutic insight into means for altering stem cell fates for the amelioration of genetic and acquired neuropathologic disease.